Project Summary The Clinical Research Support Core 3 is dedicated to two major efforts. First, we are responsible for obtaining human samples from patients with myeloid malignancies at the time of diagnosis and relapse as well as at specific timepoints in clinical trials for ancillary studies. The diagnostic and relapse samples are used to perform research in each of the four projects. Thus, human leukemic blasts can be assayed for their ability to undergo apoptosis in response to various agents are described in Project 1 including BH3 profiling, both standard and dynamic. In Project 2 the importance of CBL in leukemogenesis will be assessed; the studies conducted in the Ebert lab will elucidate how downstream pathways activated by this mutation may represent therapeutic targets. Project 3 investigates the role of SALL4B in leukemia. The Armstrong/Fisher labs (Project 4) are investigating transcription factor biology relevant to mechanism of leukemogenesis in MLL rearranged leukemia. We anticipate that menin inhibition in combination with either lenalidomide and/or venetoclax will have therapeutic potential. Clinical Research Support Core 3 will be obtaining samples from patients at various stages of their disease who have signed consent for 01-206 which allows for sample banking. We will obtain these samples and transfer them to Biospecimen Core 1 for annotation and availability for scientists in the projects. The second major goal of the Core 3 is to perform clinical trials emanating from science described in the grants. We anticipated three major clinical trials during the grant funding period. In years 2 and 3, we expect that we will be performing a trial dedicated to confirming the dynamic BH3 profiling will allow selection of specific kinase inhibitors to be combined with venetoclax in the treatment of patients with advanced relapsed/refractory AML. We plan to further compare the outcome of patients treated with a kinase inhibitor plus venetoclax with those treated with ?standard? venetoclax plus hypomethylated agent. Project 2 will lead to a clinical trial involving venetoclax in combination with dasatinib, capable of inhibiting the LYN/SRC pathway activated in cells with a CBL mutation. Preliminary data suggests that menin in combination with either lenalidomide and/or venetoclax may be synergistic in MLL rearranged leukemia-which will lead to a clinical trial toward the end of the funding period. The clinical trial designs including the timing and processing of ancillary samples to confirm target engagement, will be informed with the assistance of Biostatistical Core 2. Biostatistical Core 2 will also assist in the analysis and publication of these clinical trials. It is hoped that through collection of carefully annotated samples for use in relevant assays within the projects will lead to a greater understanding of leukemia biology, and perhaps lead to additional targets that can be exploited. The clinical trials will hopefully improve the outcome of patients with leukemia.